Project Summary Candidate: Bethany Klopfenstein, MD, is completing her fellowship in Endocrinology at Oregon Health &Science University (OHSU). This proposal will promote her scientific development and laboratory skills as she transitions into an independent academic, patient-oriented, clinical investigator. Her immediate career goals are to solidify her training in clinical research and develop new laboratory techniques for the study of cortisol metabolism. Her long-term goal is to develop an independent research career in the field of cortisol metabolism in insulin resistance. To accomplish these objectives, she will participate in a comprehensive didactic curriculum and perform the studies described in the research plan. Environment: OHSU has strong interdisciplinary training programs in both clinical and basic science research, including the Human Investigations Program funded by a K30 award. The 12,500 square foot OHSU General Clinical Research Center (GCRC) includes state-of-the-art outpatient and inpatient units, as well as a Core Laboratory, Bionutrition Unit, Bioinformatics Core and biostatistics support. Research Project: The overall goal of this research project is to investigate the relationships between cortisol metabolism, fat patterning, glucose metabolism, and adrenal androgens using the model of polycystic ovary syndrome (PCOS). Specific Aim 1 is a cross-sectional study designed to examine relationships between insulin sensitivity, central (visceral) obesity, androgen levels, and cortisol regulation (both at the systemic level of the hypothalamic-pituitary-adrenal (HPA) axis and locally in adipose tissue by the enzyme 11 betahydroxysteroid dehydrogenase type 1 (HSD 1) in women with PCOS and controls. Specific Aim 2 will prospectively test the novel hypothesis that insulin sensitizing agents improve body fat distribution and androgen levels in women with PCOS in part through reductions in HPA axis and adipocyte HSD 1 activity. Relevance: Individuals with central obesity, such as women with PCOS, are at high risk for developing infertility, diabetes, and heart disease. Abnormalities in cortisol metabolism may contribute to these comorbidities. Studies proposed here will improve our understanding of the regulation of cortisol metabolism, central obesity and insulin resistance. These findings may lead to new tools for managing PCOS.